This project is designed to develop a basic understanding of the pathogenesis of retrovirus-induced immunodeficiency with successful prevention and treatment of disease being the ultimate goals. The LP-BM5 mixture of murine leukemia viruses (MuLV) induces an immunodeficiency syndrome termed mouse AIDS or MAIDS in mice of susceptible strains. Previous in vitro studies suggested that the disease-causing defective virus in this mixture exerts a superantigen-like effect. In vivo evidence for a superantigen effect was provided by the observation of preferential activation and expansion of Vbeta5+ CD4+ T cells during the early stages of MAIDS. Genes of the major histocompatibility complex are major determinants of susceptibility or resistance to MAIDS. In resistant strains, their effects are mediated by induction of protective CD8+ T cell dependent immunity in resistant mice in association with a Th1 pattern of cytokine expression (IL-2, IFN-gamma) by CD4+ cells. In susceptible mice, a Th2 pattern of cytokines was found to predominate (IL-4, IL-10). These polarized responses to infection may be driven by interaction of the defective virus antigen with various MHC haplotypes and nonspecific responses of the immune system including production of IL-12 and TNF-alpha by macrophages. Studies are in progress to manipulate the immune system of MAIDS-susceptible mice towards a Th1 response to induce resistance to disease. Additional studies are directed at defining other parameters of disease susceptibility using a series of gene knockout and transgenic mice. Preliminary studies demonstrate that disease does not develop in mice lacking MHC class II molecules or in mice lacking B cells, strongly supporting the suggestion that the disease is driven by association of viral antigen/MHC class II complexes specifically on B cells.